Version May 2024
INTRODUCTION — Roseola infantum (also known as exanthem subitum, sixth disease, pseudorubella, exanthem criticum, and three-day fever) is caused by the B variant of human herpesvirus 6 (HHV-6). It is a clinical syndrome characterized by three to five days of high fever (may exceed 40°C [104°F]) that resolves abruptly and is followed by development of a rash (picture 1).
The clinical manifestations, diagnosis, and treatment of roseola infantum will be reviewed here. The virology, pathogenesis, epidemiology, and other clinical manifestations of HHV-6 in children are discussed separately. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection" and "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment".)
MICROBIOLOGY — Human herpesvirus 6B (HHV-6B) is the most frequent cause of roseola [1,2]. Other causes include HHV-7, enteroviruses (coxsackieviruses A and B, echoviruses), adenoviruses, and parainfluenza virus type 1 [1,3,4].
EPIDEMIOLOGY
Prevalence and seasonality — Roseola is an illness of young children, with a peak prevalence between 7 and 13 months [5]. Ninety percent of cases occur in children younger than two years. Roseola occurs equally in males and females [1,6].
It occurs throughout the year, but the peak incidence is in the spring and fall seasons [1,5].
Transmission — Most cases of roseola occur sporadically, without known exposure [1,5,7]. However, secondary cases and horizontal transmission have been reported [1,8,9]. Asymptomatic shedding of human herpesvirus 6 (HHV-6) variant B respiratory droplets by older siblings and parents has been responsible for transmission to young infants. Transmission from household rather than community contacts is supported by studies from Japan and Turkey demonstrating that the incidence of roseola did not change during the coronavirus disease 2019 pandemic, in contrast to the incidence of other common respiratory infections (eg, influenza, respiratory syncytial virus) [10-13].
The modes of transmission, duration of shedding, and incubation periods vary depending upon the etiologic agent [3]. HHV-6 most likely is transmitted by asymptomatic shedding of virus in secretions of close contacts [5,14,15]. The duration of shedding for HHV-6 is not known but is thought to be lifelong, with an increase in viral shedding in the convalescent phase [14,16]. The mean incubation period for HHV-6B is 9 to 10 days [15]. (See "Virology, pathogenesis, and epidemiology of human herpesvirus 6 infection", section on 'Incubation period and transmission'.)
Transmission of less common causes of roseola is discussed separately:
Human herpesvirus 7 (see "Human herpesvirus 7 infection", section on 'Epidemiology')
Enterovirus (see "Enterovirus and parechovirus infections: Epidemiology and pathogenesis", section on 'Transmission')
Adenovirus (see "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection", section on 'Transmission')
Parainfluenza viruses (see "Parainfluenza viruses in children", section on 'Transmission and incubation period')
CLINICAL FEATURES
Clinical course — The clinical course of roseola is characteristic: three to five days of fever that resolves abruptly and is followed by development of a rash.
Febrile phase — Classical roseola begins with a fever that may exceed 40°C (104°F) and lasts for three to five days (mean 3.8 days) [5-7,17,18]. The fever often is accompanied by irritability, although most children with roseola are otherwise well-appearing, active, and alert [1,5,7].
A number of other clinical manifestations during the febrile phase of illness have been described in children with roseola [1,6,18-21]. In two case series of children with primary HHV-6 infection and rash or roseola, other clinical manifestations included palpebral conjunctivitis (25 percent), edematous eyelids (30 percent), acute otitis media/inflamed tympanic membrane (8 percent), uvulopalatoglossal junctional macules or ulcers (sometimes called Nagayama spots, 65 percent), rhinorrhea (61 percent), cough (62 percent) vomiting (21 percent), diarrhea (24 to 68 percent), and a bulging fontanelle (26 percent) [6,21]. Less common clinical manifestations include hepatitis, thrombocytopenia, mononucleosis-like syndrome, colitis, or myocarditis [22-24]. The combination of high fever and bulging fontanelle frequently results in an evaluation for possible meningitis.
Cervical, postauricular, and/or occipital lymphadenopathy are common, typically occurring two to four days after the onset of fever [6]. In two case series of patients with primary HHV-6 infection and rash and/or roseola, approximately one-third of patients had cervical lymphadenopathy [6,21].
Rash — As the child's fever abates, a blanching macular or maculopapular rash develops, starting on the neck and trunk and spreading to the face and extremities (picture 1). Occasionally the rash is vesicular. It is generally nonpruritic [18]. The rash typically persists for one to two days but occasionally may come and go within two to four hours [1,5,25]. In children receiving antibiotics, the later onset of the rash frequently is misinterpreted as a drug allergy. (See 'Differential diagnosis' below.)
The pathogenesis of the rash is unclear [1]. It develops after the viremic phase of illness, coincident with the development of antibody to HHV-6, suggesting that it may result from antigen-antibody complexes [2,26].
Laboratory features — Laboratory investigation is seldom necessary for patients with classic roseola. However, it may be undertaken in children with atypical features (eg, simultaneous fever and rash) or as part of the evaluation of fever. (See "Fever without a source in children 3 to 36 months of age: Evaluation and management".)
Laboratory features of roseola may include:
●Neutropenia and atypical lymphocytosis – Children with roseola may have relative neutropenia and mild atypical lymphocytosis [1,5,27-29]. Early in the febrile period, the white blood cell count may be elevated but reaches its nadir (frequently in the range of 3000 cells/microL) by day 3 to 6 of illness, then gradually returns to normal over the following 7 to 10 days.
●Thrombocytopenia – Children with roseola also may have thrombocytopenia, which is thought to be caused by bone marrow suppression rather than immune-mediated peripheral consumption [29].
●Sterile pyuria – Children with roseola may have sterile pyuria. In a retrospective study from a single institution, 13 percent of 158 children with roseola had sterile pyuria [20]. During the febrile phase, urinary tract infection (UTI) may be a diagnostic consideration in children with pyuria. The differentiation of roseola from UTI is discussed below. (See 'Fever and pyuria' below.)
Complications — Roseola is usually a benign, self-limited illness. Complications may include seizures, aseptic meningitis, encephalitis, and thrombocytopenic purpura. Seizures generally are related to fever. Febrile seizures occur in approximately 10 to 15 percent of children with primary HHV-6B infection [15]. (See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Clinical manifestations'.)
DIAGNOSIS — Roseola is diagnosed clinically based on the characteristic features: fever for three to five days followed by abrupt defervescence and development of a rash in a young child [1,3].
Laboratory evaluation is seldom necessary. In most patients with roseola caused by human herpesvirus 6 (HHV-6), by the time the rash appears, viremia has resolved [2,26]. (See 'Rash' above.)
Virologic studies may be warranted in immunocompromised patients and those with an atypical presentation or complications. The diagnostic approach for potential pathogens is discussed separately:
●HHV-7 (see "Human herpesvirus 7 infection", section on 'Diagnosis')
●Enterovirus (see "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Laboratory diagnosis')
●Adenovirus (see "Diagnosis, treatment, and prevention of adenovirus infection")
●Parainfluenza virus type 1 (see "Parainfluenza viruses in children", section on 'Diagnosis')
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of the roseola rash includes several other infectious exanthems and drug allergy (figure 1) [5]. Roseola generally can be distinguished from these conditions by epidemiologic or clinical features (eg, age group, temporal relation between fever and rash). Roseola also must be distinguished from urinary tract infection (UTI) in children who present with fever before the onset of rash and are found to have pyuria during the evaluation of fever.
Establishing the correct diagnosis as roseola can alleviate caregiver concerns and limit unnecessary evaluations and antibiotic therapy [30,31].
Infectious exanthems — The infectious exanthems to be considered in the differential diagnosis of roseola include (figure 1) [3]:
●Rubella (picture 2) is characterized by simultaneous occurrence of low-grade fever and rash. The rash classically begins on the face and spreads down the body. Rubella occurs in children who are unimmunized or underimmunized. (See "Rubella".)
●Rubeola (measles) (picture 3), which is distinguished by a prodrome of fever followed by coryza, cough, and Koplik spots (picture 4). The rash classically begins on the face and spreads down the body; it begins as small lesions that enlarge and coalesce. Rubeola occurs in children who are unimmunized or underimmunized. (See "Measles: Clinical manifestations, diagnosis, treatment, and prevention".)
●Enteroviral infections, which usually occur in epidemics in the spring, summer, and fall (typically with a peak in mid- to late summer) and occur in children of all ages, not just young children. Hand, foot, and mouth disease (HFMD) is the classic enteroviral rash (picture 5). The oral enanthem (picture 6A-B) is a characteristic feature of HFMD; prodromal symptoms usually are absent but may include low-grade fever. (See "Enterovirus and parechovirus infections: Clinical features, laboratory diagnosis, treatment, and prevention", section on 'Laboratory diagnosis' and "Hand, foot, and mouth disease and herpangina".)
●Erythema infectiosum is characterized by a rash that is prominent on the cheeks (picture 7A-B). The facial rash may be followed by a "lacelike" rash (reticulated blanching erythema) on the trunk and extremities (picture 8), which may recur. Erythema infectiosum usually affects school-age children. Most children with erythema infectiosum have minimal or no symptoms; however, they may have a nonspecific prodrome (eg, fever, coryza, headache, nausea, diarrhea). (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
●Scarlet fever is characterized by a rash that is diffuse, erythematous, and sandpaper-like (picture 9). The rash occurs with or is preceded by pharyngitis. Children with scarlet fever may develop confluent petechiae in the antecubital fossae (Pastia lines). Resolution of the rash is followed by desquamation and/or frank peeling. (See "Complications of streptococcal tonsillopharyngitis", section on 'Scarlet fever'.)
Drug allergy — Drug allergy is an important consideration in children with fever who are treated with antibiotics and then develop a rash (picture 10). Clinical features that help to distinguish drug allergy from roseola include the duration of rash (longer in drug allergy than in roseola), and pruritus (present in drug allergy, not in roseola) [1,18]. (See "Penicillin allergy: Immediate reactions".)
Fever and pyuria — UTI is a consideration among infants who present with fever before the onset of the characteristic roseola rash and are found to have pyuria during the evaluation of fever. (See 'Laboratory features' above.)
Urine culture results will ultimately differentiate UTI from roseola in such children. A retrospective study of 158 young children (one month to three years) with roseola and 143 young children with UTI identified presenting clinical and laboratory findings more suggestive of UTI than roseola [20]. Peripheral white blood cell (WBC) count >10,000 cells/microL was the most helpful single finding (occurring in 70 percent of children with UTI and only 4 percent of those with roseola). Additional findings that were more common among children with UTI than roseola included male sex, age <6 months, C-reactive protein >0.5 mg/dL (5 mg/L), and fever of <4 days duration at presentation. Although not examined in the study, a positive nitrite test by dipstick analysis is highly suggestive of UTI. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Rapidly available tests'.)
Pending urine culture results, decisions regarding empiric antibiotics are best made on a case-by-case basis based upon the probability of UTI, which is determined by demographic and clinical factors (eg, age, circumcision status, urinary tract anomalies, etc) [32]. To prevent unnecessary use of antibiotics in children in whom both UTI and roseola are being considered, it may be reasonable to withhold antibiotics pending urine culture results among those who are well-appearing, ≥6 months of age, have peripheral WBC count between 5000 and 10,000 cells/microL, and negative nitrites on dipstick analysis. (See "Urinary tract infections in infants older than one month and children less than two years: Acute management, imaging, and prognosis", section on 'Determining need for early empiric antibiotic therapy'.)
TREATMENT — In most cases, roseola is a benign and self-limited disease. Treatment is supportive [3]. Fever can be controlled with antipyretics (eg, acetaminophen) if it is associated with discomfort. The rash resolves without treatment. (See "Fever in infants and children: Pathophysiology and management", section on 'Management of fever'.)
Associated clinical features should be treated as indicated (eg, ensuring adequate fluid intake for infants with diarrhea or vomiting).
PROGNOSIS — Most children with roseola recover spontaneously without sequelae.
PREVENTION
Hygiene — Roseola may be caused by several viruses. Transmission of human herpesvirus 6, the most common cause, probably results from asymptomatic shedding of virus in secretions of close contacts, which is difficult to prevent [15]. The other viruses that cause roseola typically are spread through respiratory secretions or the fecal-oral route. Simple hygienic measures, such as handwashing, may help to prevent spread. (See "Enterovirus and parechovirus infections: Epidemiology and pathogenesis" and "Diagnosis, treatment, and prevention of adenovirus infection", section on 'Prevention'.)
Child care — There is no recommended period of exclusion from out-of-home child care for children with roseola [33]. Children with sporadic cases of roseola are not considered to be contagious [1,5].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)
●Basics topic (see "Patient education: Roseola (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Microbiology and epidemiology – Human herpesvirus 6 (HHV-6) is the most frequent cause of roseola. Other causes include HHV-7, enteroviruses, adenovirus, and parainfluenza virus type 1. (See 'Microbiology' above.)
Roseola is an illness of young children, with a peak prevalence between 7 and 13 months. It occurs throughout the year. Most cases occur sporadically without known exposure. (See 'Epidemiology' above.)
●Clinical and laboratory features – Roseola classically begins with three to five days of fever that may exceed 40°C (104°F); as the fever abates, a blanching macular or maculopapular rash develops, starting on the neck and trunk and spreading to the face and extremities (picture 1). (See 'Clinical course' above.)
Laboratory investigation is seldom necessary for patients with classic roseola. However, it may be undertaken in children with atypical features or as part of the evaluation of fever. Laboratory features of roseola include relative neutropenia and mild atypical lymphocytosis. Children with roseola also may have thrombocytopenia or sterile pyuria. (See 'Laboratory features' above.)
●Diagnosis and differential diagnosis – Roseola is diagnosed clinically based on the characteristic features: fever for three to five days followed by abrupt defervescence and development of a rash in a young child (picture 1). (See 'Diagnosis' above.)
The differential diagnosis of roseola includes several other infectious exanthems and drug allergy (figure 1). (See 'Differential diagnosis' above.)
●Management and prevention – Roseola is usually a benign self-limited disease. Treatment is supportive (eg, control of fever if it is associated with discomfort). (See 'Treatment' above.)
Standard hygienic measures, such as handwashing, may help to prevent spread of the viral pathogens that cause roseola. There is no recommended period of exclusion from out-of-home child care for children with roseola. (See 'Prevention' above.)
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